Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

Abstract

The activin receptor type IIB (ActRIIB) is a transmembrane receptor for transforming growth factor-β superfamily members, including myostatin, that are involved in the negative regulation of skeletal muscle mass. We tested the translational hypothesis that blocking ligand binding to ActRIIB for 12 weeks would stimulate skeletal muscle growth and improve muscle function in the mdx mouse. ActRIIB was targeted using a novel inhibitor comprised of the extracellular portion of the ActRIIB fused to the Fc portion of murine IgG (sActRIIB), at concentrations of 1.0 and 10.0 mg/kg(-1) body weight. After 12 weeks of treatment, the 10.0 mg/kg(-1) dose caused a 27% increase in body weight with a concomitant 33% increase in lean muscle mass. Absolute force production of the extensor digitorum longus muscle ex vivo was higher in mice after treatment with either dose of sActRIIB, and the specific force was significantly higher after the lower dose (1.0 mg/kg(-1)), indicating functional improvement in the muscle. Circulating creatine kinase levels were significantly lower in mice treated with sActRIIB, compared with control mice. These data show that targeting the ActRIIB improves skeletal muscle mass and functional strength in the mdx mouse model of DMD, providing a therapeutic rationale for use of this molecule in treating skeletal myopathies.

Effects of sActRIIB therapy on skeletal muscle mass in control mdx mice and mdx mice treated with 1.0 mg/kg−1 or 10.0 mg/kg−1 sActRIIB. Significant increases in absolute skeletal muscle mass were observed at one or both doses for gastrocnemius (A), tibialis anterior (B), and quadriceps (C) muscles, compared with control mdx mice. Normalized to body weight, however, no significant change in skeletal muscle mass was observed for gastrocnemius muscle (D) at either dose, compared with control mice. A significant decrease was observed at the lower dose for tibialis anterior (E) and quadriceps (F) muscles; at the higher dose, significant increase was observed in the tibialis anterior (E) muscle. *P < 0.05; **P < 0.001; ***P < 0.0001.

Effects of sActRIIB therapy on EDL weight and CSA in control mdx mice and in mdx mice treated with 1.0 mg/kg−1 or 10.0 mg/kg−1 sActRIIB. Significant increases were observed at both doses in absolute EDL weight (A) and at the higher dose in normalized EDL weight (B), and EDL whole-muscle cross-sectional area (CSA) (C). The dashed line (A–C)indicates values for untreated, age-matched wild-type BL/10 mice. D and E: Histograms from single-fiber CSA analysis reveal a shift to the right for the higher dose (D). *P < 0.05; ***P < 0.001.